Development of a risk scoring system for prognostication in HIV-related toxoplasma encephalitis.

BACKGROUND: This study aims to evaluate specific risk factors influencing prognosis of HIV-infected patients with toxoplasma encephalitis (TE) in order to develop a prognostic risk scoring system for them. METHODS: This is a six-center retrospective study of hospitalized HIV/TE patients. Data including six-week mortality after diagnosis, baseline characteristics, clinical features, laboratory tests and radiological characteristics of eligible patients were assimilated for risk model establishing. RESULTS: In this study, the six-week mortality among 94 retrospective cases was 11.7% (11/94). Seven specific risk factors, viz. time from symptom onset to presentation, fever, dizziness, CD4+ T-cell counts, memory deficits, patchy brain lesions, and disorders of consciousness were calculated to be statistically associated with mortality. A criterion value of '9' was selected as the optimal cut-off value of the established model. The AUC of the ROC curve of this scoring model was 0.976 (p < 0.001). The sensitivity and specificity of the risk scoring model was 100.0 and 86.9%, respectively, which were 81.8 and 94.1% of this scoring model in the verification cohort, respectively. CONCLUSIONS: The developed scoring system was established with simple risk factors, which also allows expeditious implementation of accurate prognostication, and appropriate therapeutic interventions in HIV-infected patients with TE.

Incidence, presentation and outcome of toxoplasmosis in HIV infected in the combination antiretroviral therapy era.

BACKGROUND: HIV-associated incidence and prognosis of cerebral toxoplasmosis (CTX) is not well established during later years. METHODS: From the Danish HIV Cohort Study, we identified 6325 HIV-infected individuals. We assessed incidence, mortality, predictive and prognostic factors of CTX during the pre-combination antiretroviral therapy (pre-cART; 1995-1996) and cART-era (1997-2014). Adjusted incidence rate ratios (aIRR), mortality rate ratios (aMRR) and 95% confidence intervals (CI) were assessed using Poisson regression analysis. RESULTS: CTX IR was 1.17/1000 PYR (95% CI 0.93-1.47). We observed no change in CTX-risk in the first year after HIV-diagnosis, but a substantial reduction in mortality in the first 3 months after CTX diagnosis when comparing the cART-era to the pre-cART-era; {(aIRR: 0.79; 95% CI: 0.37-1.72) (aMRR: 0.15; 95% CI: 0.06-0.38)}. For individuals surviving the first year after HIV-diagnosis or the first 3 months after CTX-diagnosis, IRR and MRR had declined to minimal levels {(aIRR: 0.06; 95% CI: 0.03-0.10); (aMRR: 0.02; 95% CI: 0.01-0.05)}. Three years after CTX-diagnosis 30% of the patients still had neurological deficits. CONCLUSION: Although, CTX remains an important cause of morbidity and mortality in the cART-era, with high prevalence of neurological sequelae, incidence and mortality has largely declined, especially among those surviving the first year after diagnosis.

Safety and diagnostic value of brain biopsy in HIV patients: a case series and meta-analysis of 1209 patients.

Early brain biopsy may be indicated in HIV patients with focal brain lesion. This study aimed to evaluate and compare the safety and diagnostic value of brain biopsy in HIV patients in the pre-highly active antiretroviral therapy (HAART) versus post-HAART era via meta-analysis. Appropriate studies were identified per search criteria. The local database was retrospectively reviewed to select a similar patient cohort. Patient demographics, brain biopsy technique, histopathology and patient outcomes were extracted from each study. Study-specific outcomes were combined per random-effects model. Outcomes were compared between the pre-HAART and post-HAART era. Correlations between outcomes and baseline characteristics were assessed via meta-regression analysis. The proportions of histopathological diagnosis were tabulated and compared between the pre- and post-HAART era. Survival analysis was performed for patients in the post-HAART era. A total of 26 studies (including the local database) with 1209 patients were included in this meta-analysis. The most common indications for brain biopsy were diagnosis unlikely to be toxoplasmosis (n=8, 42.1%), focal brain lesion (n=5, 26.3%) or both (n=3, 15.8%). The weighted proportions for diagnostic success were 92% (95% CI 90.0% to 93.8%), change in management 57.7% (45.9% to 69.1%) and clinical improvement 36.6% (26.3% to 47.5%). Morbidity and mortality were 5.7% (3.6% to 8.3%) and 0.9% (0.3% to 1.9%), respectively. Diagnostic success rate was significantly higher in the post-HAART than the pre-HAART era (97.5% vs 91.9%, p=0.047). The odds ratio (OR) for diagnostic success in patients with contrast-enhanced lesions was 2.54 ((1.25 to 5.15), p<0.01). The median survival for HIV patients who underwent biopsy in the post-HAART era was 225 days (90-2446). Brain biopsy in HIV patients is safe with high diagnostic yield. Early brain biopsy should be considered in patients without classic presentation of toxoplasmosis encephalitis.

[Follow-up study of HIV-infected patients with prior cerebral toxoplasmosis].

AIM: To assess follow-up study results in human immunodeficiency virus (HIV)-infected patients with prior cerebral toxoplasmosis (CT). SUBJECT AND METHODS: Follow-up study results were assessed in HIV-infected patients with prior CT. RESULTS: The fate of only 97 out of 137 (66% of the hospitalized) patients discharged from hospital is known, as 40 convalescents have been lost to follow up. Thereafter, relapses developed in 19 patients, of whom 6 died. Eleven more patients with HIV infection died due to its progression and development of other secondary lesions. Five more patients died from narcotic overdose, staphylococcal sepsis, and acute pancreatic necrosis. The main peak of fatal outcomes was within the first 2 years after discharge. 3.5-year survival rates after TC were 75%. The causes of recurrent and progressive HIV infection were non-compliance with secondary prevention of CT and low adherence to an antiretroviral therapy regimen, the blame of which fell not only on the patients, but also their attending physicians and specialists who had advised how to enhance treatment motivation. CONCLUSION: Further follow-up of convalescent CT patients calls for closer attention to the possible development of recurrences within the first three years after discharge in particular, regardless of CD4 cell counts.

Alternative treatment approach to cerebral toxoplasmosis in HIV/AIDS: experience from a resource-poor setting.

The current standard treatment for cerebral toxoplasmosis (pyrimethamine/sulfadiazine) often encounters problems of poor tolerability, adverse effects, frequent dropouts and non-availability of pyrimethamine/sulfadiazine in some parts of India. We have had to use the combination of two effective alternative agents for toxoplasmosis, cotrimoxazole and clindamycin, on compassionate grounds. This retrospective observational study reports superior efficacy and better tolerability of cotrimoxazole/clindamycin compared to the recommended regimen. Primary end-point (complete response) was defined as more than 50% improvement of clinical status or more than 50% decrease in the size of brain lesions after two weeks of treatment initiation. Complete response occurred more commonly with cotrimoxazole/clindamycin than with pyrimethamine/sulfadiazine group (80% vs. 31.25%, respectively, relative risk 2.56, 95% confidence interval: 1.21-5.43). There was a trend towards higher on-treatment mortality in the pyrimethamine/sulfadiazine group in comparison to the cotrimoxazole/clindamycin (mortality rate 37.5% in pyrimethamine/sulfadiazine vs 12% in cotrimoxazole/clindamycin, p = 0.07, relative risk = 3.125, 95% confidence interval: 0.91-10.75). Overall, 62.5% (10/16) of patients on pyrimethamine/sulfadiazine suffered drug-related adverse reactions compared to 24% (6/25) on cotrimoxazole/clindamycin (p = 0.02, relative risk = 2.60, 95% confidence interval: 1.17-5.76). The commonest complication of pyrimethamine/sulfadiazine was severe thrombocytopenia with major bleeding (4/16, 25%). We propose that the new combination chemotherapy, which is widely available, effective and safe, can be used in developing countries.

Hyponatremia, acute kidney injury, and mortality in HIV-related toxoplasmic encephalitis

BACKGROUND: There are no reports on hyponatremia and acute kidney injury (AKI) involved in the course of HIV-related toxoplasmic encephalitis (TE). The main objective of this study was to describe the occurrence of hyponatremia and its relationship with AKI and mortality in HIV-related toxoplasmic encephalitis (TE). METHODS: This was a retrospective cohort study on patients with HIV-related TE. AKI was considered only when the RIFLE (risk, injury, failure, loss, end-stage) criterion was met, after the patient was admitted. RESULTS: A total of 92 patients were included, with a mean age of 36 ± 9 years. Hyponatremia at admission was observed in 43 patients (46.7%), with AKI developing in 25 (27.1%) patients during their hospitalization. Sulfadiazine was the treatment of choice in 81% of the cases. Death occurred in 13 cases (14.1%). Low serum sodium level correlated directly with AKI and mortality. Male gender (OR 7.89, 95% CI 1.22-50.90, p = 0.03) and hyponatremia at admission (OR 4.73, 95% CI 1.22-18.30, p = 0.02) were predictors for AKI. Independent risk factors for death were AKI (OR 8.3, 95% CI 1.4-48.2, p < 0.0001) and hyponatremia (or 9.9, 95% ci 1.2-96.3, p < 0.0001). CONCLUSION: AKI and hyponatremia are frequent in TE. Hyponatremia on admission is highly associated with AKI and mortality.

Hyponatremia, acute kidney injury, and mortality in HIV-related toxoplasmic encephalitis.

BACKGROUND: There are no reports on hyponatremia and acute kidney injury (AKI) involved in the course of HIV-related toxoplasmic encephalitis (TE). The main objective of this study was to describe the occurrence of hyponatremia and its relationship with AKI and mortality in HIV-related toxoplasmic encephalitis (TE). METHODS: This was a retrospective cohort study on patients with HIV-related TE. AKI was considered only when the RIFLE (risk, injury, failure, loss, end-stage) criterion was met, after the patient was admitted. RESULTS: A total of 92 patients were included, with a mean age of 36±9 years. Hyponatremia at admission was observed in 43 patients (46.7%), with AKI developing in 25 (27.1%) patients during their hospitalization. Sulfadiazine was the treatment of choice in 81% of the cases. Death occurred in 13 cases (14.1%). Low serum sodium level correlated directly with AKI and mortality. Male gender (OR 7.89, 95% CI 1.22-50.90, p = 0.03) and hyponatremia at admission (OR 4.73, 95% CI 1.22-18.30, p = 0.02) were predictors for AKI. Independent risk factors for death were AKI (OR 8.3, 95% CI 1.4-48.2, p < 0.0001) and hyponatremia (OR 9.9, 95% CI 1.2-96.3, p < 0.0001). CONCLUSION: AKI and hyponatremia are frequent in TE. Hyponatremia on admission is highly associated with AKI and mortality.

Neurologic outcomes and adjunctive steroids in HIV patients with severe cerebral toxoplasmosis.

OBJECTIVES: Cerebral toxoplasmosis remains a common neurologic complication in patients with AIDS. In this study, we aimed to characterize the prognosis of patients with HIV infection with severe forms of cerebral toxoplasmosis and to investigate the effects of adjunctive steroids on outcomes. METHODS: We carried out a retrospective cohort study (2000-2011) on consecutive patients with cerebral toxoplasmosis admitted to the medical intensive care unit (ICU) of 5 hospitals. Functional prognosis was graded at 3 months using the modified Rankin Scale (mRS). RESULTS: We studied 100 patients with a CD4 cell count of 25 (8-62) cells/µL and a Glasgow Coma Scale (GCS) score of 11 (6-14). At follow-up, 51 patients had an mRS score of 0-2 (functional independence), 30 had an mRS score of 3-5 (severe disability), and 19 had an mRS score of 6 (death). Compared with other specific treatments, the use of pyrimethamine-sulfadiazine was associated with improved survival (p = 0.03). Two factors present at ICU admission were independently associated with a poor outcome (mRS score >2) at 3 months: a CD4 cell count <25 cells/µL (odds ratio [OR] 2.7, 95% confidence interval [CI] 1.1-6.7) and a GCS score ≤8 (OR 3.1, 95% CI 1.2-7.7). In patients treated with pyrimethamine-sulfadiazine, the use of adjunctive steroids to treat cerebral edema associated with focal lesions appeared safe but was not associated with better neurologic outcomes. CONCLUSION: Severe forms of cerebral toxoplasmosis in patients with HIV infection are characterized by a good prognosis in approximately 50% of cases. Profound immunodepression and impaired consciousness represent major determinants of outcome. In our study, the benefit of adjunctive steroids to treat cerebral edema could not be demonstrated.

Causes of mortality associated with HIV/AIDS in health-care facilities in Togo: a six-month prospective study.

In order to determine the rate and the different causes of mortality associated with HIV/AIDS in health-care facilities we conducted a prospective study between 1 April and 30 September 2010 in the six health regions of Togo. We rationalized the choice of the healthcare facilities in order to cover the entire national territory. During the study period, 24,054 patients were hospitalized. HIV serology was positive in 1065 (18.2%) of the 5865 tested patients. Of the 24,054 patients, we recorded 2551 deaths (10.6%), including 309 HIV-infected patients (5.2%). The mortality rate associated with HIV/AIDS was 1.3% of the total number of inpatients and 5.3% of the number of patients tested for HIV. The mortality rate among HIV-infected patients was 29%. The causes of death in patients infected with HIV/AIDS were mainly anaemia and cerebral toxoplasmosis. This study shows that mortality associated with HIV/AIDS in health-care facilities in Togo remains relatively high.

[Treatment of neuro-AIDS on a neurological intensive care unit: epidemiology and predictors of outcome]. / Behandlung von Neuro-Aids auf der neurologischen Intensivstation : Epidemiologie, Outcome und Prädiktoren des Verlaufs.

BACKGROUND: Investigations concerning the outcome for patients suffering from neuro-AIDS treated on a neurological intensive care unit and specific predictors indicating "dead" were analyzed. MATERIAL AND METHODS: A total of 56 patients with a mean age of 39 ± 0.7 years, a mean CD4+ cell count of 130 ± 166 CD4+ cells/µl and viral load of 146,520 ± 198,059 copies/ml were treated on a neurological intensive care unit due to different forms of neuro-AIDS. RESULTS: Of the patients, 34% were immigrants of whom 74% came from sub-Saharan regions. In 57% of the patients the diagnosis of HIV infection was made during therapy on the neurological intensive care unit. The median for the time between diagnosis of HIV infection and the treatment on the neurological intensive care unit was 8 days for immigrants and 10 years for residents. The most common manifestations of neuro-AIDS were cerebral toxoplasmosis, cryptococcosis and progressive multifocal leukoencephalopathy (PML). Fifty per cent of the patients (n=28) died during treatment on the neurological intensive care unit. Negative predictors for the outcome "dead" were (a) artificial ventilation, (b) antiretroviral naïve immigrant, (c) primary cerebral lymphoma and (d) missing antiretroviral therapy as a result of admission to the intensive care unit. DISCUSSION: The rate of death during treatment of neuro-AIDS on a neurological intensive care unit is much higher than during treatment of internal medicine problems of HIV infection. Antiretroviral naïve immigrants show a much higher rate of death compared to residents in Germany. A lot of research and effort is necessary to improve the availability of the Highly Active Anti-Retroviral Therapy (HAART) worldwide in order to improve the outcome especially for immigrants with neuro-AIDS treated on a neurological intensive care unit.

Toxoplasmic encephalitis in an AIDS cohort at Puerto Rico before and after highly active antiretroviral therapy (HAART).

Highly active antiretroviral therapy (HAART) significantly reduced the toxoplasmic encephalitis (TE) incidence in acquired immunodeficiency syndrome (AIDS) patients. The TE incidence and mortality were evaluated in an AIDS cohort followed in Puerto Rico before, during, and after HAART implementation in the Island. Of the 2,431 AIDS studied patients 10.9% had TE diagnosis, with an incidence density that decreased from 5.9/100 person-years to 1.1/100 person-years after HAART. Cox proportional hazard analysis showed substantial mortality reduction among TE cases who received HAART. No mortality reduction was seen in those cases who received TE prophylaxis. Although this study shows a TE incidence and mortality reduction in the AIDS cohort after HAART, the incidence was higher than those reported in the United States AIDS patients. Poor TE prophylaxis compliance might explain the lack of impact of this intervention. Strengthening the diagnostic and opportune TE diagnosis and prompt initiation of HAART in susceptible patients is important to control this opportunistic infection.

Survival after neuroAIDS: association with antiretroviral CNS Penetration-Effectiveness score.

OBJECTIVE: We examined if the CNS Penetration-Effectiveness (CPE) score of antiretroviral drugs was associated with survival after a diagnosis of HIV-related encephalopathy, progressive multifocal leukoencephalopathy (PML), cerebral toxoplasmosis, or cryptococcal meningitis. METHODS: Using data from the FHDH-ANRS CO4, we compared the survival of 9,932 HIV-infected patients diagnosed with a first neurologic AIDS-defining event in the pre-combination antiretroviral therapy (cART) (1992-1995), early cART (1996-1998), or late cART (1999-2004) periods. Follow-up was subdivided (CPE < 1.5 and CPE ≥ 1.5), and relative rates (RR) of death were estimated using multivariable Poisson regression models. RESULTS: In the pre-cART and early cART periods, regimens with CPE ≥ 1.5 were associated with lower mortality after HIV-related encephalopathy (RR 0.64; 95% confidence interval [CI] 0.47-0.86 and RR 0.45; 95% CI 0.35-0.58) and after PML (RR 0.79; 95% CI 0.55-1.12 and RR 0.45; 95% CI 0.31-0.65), compared to regimens with CPE < 1.5, while in the late cART period there was no association between the CPE score and the mortality. A higher CPE score was also associated with a lower mortality in all periods after cerebral toxoplasmosis (RR 0.68, 95% CI 0.56-0.84) or cryptococcal meningitis (RR 0.50, 95% CI 0.34-0.74). Whatever the neurologic event, these associations were not maintained after adjustment on updated plasma HIV-RNA (missing, <500, ≥500 copies/mL) with RR ranging from 0.82 (95% CI 0.36-1.91) to 1.02 (0.69-1.52). CONCLUSION: At the beginning of the cART era, the CPE score was of importance for survival after severe neurologic event, while in the late cART period, the additional effect of CPE score vanished with more powerful antiretroviral regimens associated with plasma viral load control.

Factors associated with mortality among HIV-infected patients in the era of highly active antiretroviral therapy in southern India.

OBJECTIVE: To describe the causes of mortality among the HIV-infected in southern India in the era of highly active antiretroviral therapy (HAART). METHODS: Analyses of this patient cohort were conducted using the YRG Centre for AIDS Research and Education HIV Natural History Observational Database. Causes of death were then individually confirmed by patient chart review. RESULTS: Sixty-nine deaths occurred within the inpatient unit; 25% were female and the median age of the 69 patients was 34 years. Over half of the patients (55%) died within three months of initiating HAART. At the time of enrollment into clinical care, the median CD4 cell count was 64 cells/microl (interquartile range (IQR) 37-134). At the time of initiating HAART, the median CD4 cell count was 58 cells/microl (IQR 31-67) for patients who died within 3 months of initiating HAART and 110 cells/microl (IQR 77-189) for patients who died more than 3 months after initiating HAART. Close to three-fourths of patients (70%) died from an AIDS-defining illness (ADI). The major ADI causes of death included Pneumocystis jiroveci pneumonia (22%), extrapulmonary tuberculosis (19%), CNS toxoplasmosis (12%), and pulmonary tuberculosis (10%). A tenth of patients died from cerebrovascular infarcts. Three patients (4%) died from non-Hodgkin lymphoma. CONCLUSIONS: AIDS-related events continue to be the major source of mortality among the HIV-infected in southern India in the era of HAART. This mortality pattern justifies increased proactive efforts to identify HIV-infected patients and initiate HAART earlier, before patients present to care with advanced immunodeficiency.

Treating AIDS-associated cerebral toxoplasmosis - pyrimethamine plus sulfadiazine compared with cotrimoxazole, and outcome with adjunctive glucocorticoids.

We conducted a retrospective study of AIDS-associated cerebral toxoplasmosis. Eighteen patients received pyrimethamine plus sulfadiazine and 25 co-trimoxazole, with comparable baseline characteristics. There were no differences in clinical outcomes, but co-trimoxazole was better tolerated (p = 0.066). There was also a trend towards more deaths among patients who received glucocorticoids.

The timing of sulfadiazine therapy impacts the reactivation of latent Toxoplasma infection in IRF-8-/- mice.

The process of reactivation of latent infection with Toxoplasma gondii in immunosuppressed hosts is yet not fully understood. In the past, a number of murine models of reactivation in immunocompromised mice have been described using sulfadiazine to establish latent infection before withdrawal and subsequent reactivation. We studied the process of reactivation in brains of mice with a targeted mutation in the interferon-regulatory factor (IRF)-8 gene after withdrawal of sulfadiazine therapy. IRF-8(-/-) mice were orally infected with five cysts of the ME 49 strain of T. gondii. To allow establishment of latent infection with cyst formation, mice were treated with sulfadiazine starting either 3, 5, 6, or 7 days postinfection. Sulfadiazine was withdrawn after 14-21 days to allow reactivation. We observed that timing of sulfadiazine therapy had a marked impact on the course of infection and reactivation. Mice treated late after infection (days 5-7) showed increased mortality and decreased time to death compared to mice treated early after infection (group A). In the blood of mice with late (days 5-7) but not early (day 3) initiation of treatment, T. gondii-specific deoxyribonucleic acid was detected by polymerase chain reaction. Using double staining with stage-specific antibodies, tachyzoites were detectable in brains of mice with late initiation of sulfadiazine treatment but rarely within cysts thus indicating continued invasion of parasites across the blood-brain barrier. Intracerebral cyst rupture or bradyzoite-tachyzoite conversion was not detectable in IRF-8(-/-) mice when sulfadiazine therapy was initiated late after infection. These results indicate that continued invasion of tachyzoites rather than reactivation of latent cerebral infection impacts the course of infection in this model of reactivated toxoplasmosis. In conclusion, the timing of sulfadiazine therapy is of utmost importance for the course of infection in immunocompromised mice.

Toxoplasma gondii in individuals with schizophrenia: association with clinical and demographic factors and with mortality.

BACKGROUND: Increased rates of exposure to Toxoplasma gondii have been found in individuals with schizophrenia as compared with control groups, but the correlates of Toxoplasma exposure in schizophrenia have not been defined. METHODS: We measured IgG class antibodies to Toxoplasma gondii in 358 individuals with schizophrenia. We correlated Toxoplasma antibody status with clinical and demographic variables and examined the effect of Toxoplasma seropositivity on mortality in a follow-up period of up to 5 years. RESULTS: Individuals with schizophrenia who had serological evidence of Toxoplasma infection were more likely to be female but did not differ in age, race, total symptom score, or other demographic or clinical characteristics. However, we found that serological evidence of Toxoplasma was associated with a significantly increased risk of dying of natural causes during the follow-up period (Cox proportional hazard ratio of 4.70; 95% confidence interval, 1.27-17.31, P = .020) adjusted for age, gender, and other clinical and demographic variables. CONCLUSIONS: Toxoplasma infection may confer an increased risk for mortality from natural causes in schizophrenia. An understanding of the pathogenesis of Toxoplasma infections in individuals with schizophrenia might lead to new approaches to the management of this disorder.

Impact of opportunistic diseases on chronic mortality in HIV-infected adults in Côte d'Ivoire.

OBJECTIVE: To estimate incidence rates of opportunistic diseases (ODs) and mortality for patients with and without a history of OD among HIV-infected patients in Côte d'Ivoire. METHODS: Using incidence density analysis, we estimated rates of ODs and chronic mortality by CD4 count in patients in a cotrimoxazole prophylaxis trial in Abidjan before the highly active antiretroviral therapy (HAART) era. Chronic mortality was defined as death without a history of OD or death more than 30 days after an OD diagnosis. We used Poisson's regression to examine the effect of OD history on chronic mortality after adjusting for age, gender, and current CD4 count. RESULTS: Two hundred and seventy patients (40% male, mean age 33 years, median baseline CD4 count 261 cells/microl) were followed up for a median of 9.5 months. Bacterial infections and tuberculosis were the most common severe ODs. Of 47 patients who died, 9 (19%) died within 30 days of an OD, 26 (55%) died more than 30 days after an OD, and 12 (26%) died with no OD history. The chronic mortality rate was 31.0/100 person-years for those with an OD history, and 11.1/100 person-years for those with no OD history (rate ratio (RR) 2.81, 95% confidence interval (CI): 1.43 - 5.54). Multivariate analysis revealed that OD history remained an independent predictor of mortality (RR 2.15, 95% CI: 1.07 - 4.33) after adjusting for CD4 count, age and gender. CONCLUSIONS: Before the HAART era, a history of OD was associated with increased chronic HIV mortality in Côte d'Ivoire, even after adjusting for CD4 count. These results provide further evidence supporting OD prophylaxis in HIV-infected patients.

Stage-specific expression of surface antigens by Toxoplasma gondii as a mechanism to facilitate parasite persistence.

Toxoplasma persists in the face of a functional immune system. This success critically depends on the ability of parasites to activate a strong adaptive immune response during acute infection with tachyzoites that eliminates most of the parasites and to undergo stage conversion to bradyzoites that encyst and persist predominantly in the brain. A dramatic change in antigenic composition occurs during stage conversion, such that tachyzoites and bradyzoites express closely related but antigenically distinct sets of surface Ags belonging to the surface Ag 1 (SAG1)-related sequence (SRS) family. To test the contribution of this antigenic switch to parasite persistence, we engineered parasites to constitutively express the normally bradyzoite-specific SRS9 (SRS9(c)) mutants and tachyzoite-specific SAG1 (SAG1(c)) mutants. SRS9(c) but not wild-type parasites elicited a SRS9-specific immune response marked by IFN-gamma production, suggesting that stage-specificity of SRS Ags determines their immunogenicity in infection. The induction of a SRS9-specific immune response correlated with a continual decrease in the number of SRS9(c) cysts persisting in the brain. In contrast, SAG1(c) mutants produced reduced brain cyst loads early in chronic infection, but these substantially increased over time accompanying a hyperproduction of IFN-gamma, TNF-alpha, and IL-10, and severe encephalitis. We conclude that stage-specific expression of SRS Ags is among the key mechanisms by which optimal parasite persistency is established and maintained.